Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes
Date
2007
DOI
Authors
Larson, Martin
Atwood, Larry
Benjamin, Emelia J.
Cupples, L. Adrienne
D'Agostino, Ralph B.
Govindaraju, Diddahally
Guo, Chao-Yu
Heard-Costa, Nancy
Hwang, Shih-Jen
Version
OA Version
Citation
2007. "Framingham Heart Study 100K project: genome-wide associations
for cardiovascular disease outcomes," BMC Medical Genetics. vol. 8 issue. Suppl 1
.
Abstract
BACKGROUND:Cardiovascular disease (CVD) and its most common
manifestations - including coronary heart disease (CHD), stroke, heart failure (HF), and
atrial fibrillation (AF) - are major causes of morbidity and mortality. In many
industrialized countries, cardiovascular disease (CVD) claims more lives each year than any
other disease. Heart disease and stroke are the first and third leading causes of death in
the United States. Prior investigations have reported several single gene variants
associated with CHD, stroke, HF, and AF. We report a community-based genome-wide association
study of major CVD outcomes.METHODS:In 1345 Framingham Heart Study participants from the
largest 310 pedigrees (54% women, mean age 33 years at entry), we analyzed associations of
70,987 qualifying SNPs (Affymetrix 100K GeneChip) to four major CVD outcomes: major
atherosclerotic CVD (n = 142; myocardial infarction, stroke, CHD death), major CHD (n = 118;
myocardial infarction, CHD death), AF (n = 151), and HF (n = 73). Participants free of the
condition at entry were included in proportional hazards models. We analyzed model-based
deviance residuals using generalized estimating equations to test associations between SNP
genotypes and traits in additive genetic models restricted to autosomal SNPs with minor
allele frequency [greater than or equal to]0.10, genotype call rate [greater than or equal
to]0.80, and Hardy-Weinberg equilibrium p-value [greater than or equal to] 0.001.RESULTS:Six
associations yielded p <10-5. The lowest p-values for each CVD trait were as follows:
major CVD, rs499818, p = 6.6 x 10-6; major CHD, rs2549513, p = 9.7 x 10-6; AF, rs958546, p =
4.8 x 10-6; HF: rs740363, p = 8.8 x 10-6. Of note, we found associations of a 13 Kb region
on chromosome 9p21 with major CVD (p 1.7 - 1.9 x 10-5) and major CHD (p 2.5 - 3.5 x 10-4)
that confirm associations with CHD in two recently reported genome-wide association studies.
Also, rs10501920 in CNTN5 was associated with AF (p = 9.4 x 10-6) and HF (p = 1.2 x 10-4).
Complete results for these phenotypes can be found at the dbgap website
http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:No
association attained genome-wide significance, but several intriguing findings emerged.
Notably, we replicated associations of chromosome 9p21 with major CVD. Additional studies
are needed to validate these results. Finding genetic variants associated with CVD may point
to novel disease pathways and identify potential targeted preventive therapies.